This research focuses on a recently identified intercellular signaling pathway, the Fat pathway. The normal development and physiology of all animals, including humans, depends upon a relatively small number of highly conserved signaling pathways. The proposed studies will take advantage of powerful genetic and molecular technologies available in Drosophila, the organism in which this pathway was discovered. Available evidence suggests that Fat signaling plays a unique role in Drosophila by interpreting gradients of positional information to regulate tissue growth and polarity. Components of the pathway are conserved in humans, and are expressed in many different organ systems. Some components have already been implicated in tumor formation, both in Drosophila and in humans. This proposal has two long range goals. One is to better define the biological functions and regulation of the Fat pathway, which will be important to understanding its importance in normal development and physiology. The second is to understand how the pathway works at a molecular level. This could ultimately form a basis for manipulating the pathway to influence disease states. The first specific aim is to determine how gradients of Fat regulators influence Fat activity. These experiments will provide new insights into the regulation of Fat in developing tissues, and will test our working model for Fat pathway regulation, which explains how Fat signaling could link morphogen gradients to tissue growth. The second aim is to define the molecular basis for intracellular signaling from Fat to Warts. The experiments proposed in this aim will explore the "logic" of the Fat signaling pathway, by using functional (genetic) and physical (biochemical) approaches to explore the activities and relationships among known Fat pathway components. The third aim is to enhance our understanding of Fat signaling by identifying new pathway components, using both genetic and biochemical screens. Together these experiments will provide a framework for understanding the mechanistic basis for Fat signaling.